M. BAYARI, MD

Centre Pneumo Allergologie Pédiatrique

Casablanca, Morocco

A History of Abnormal Dentition, Hair…

Case n° 1

• 6years – Failure to thrive & no catch up – Referral for severe AD, thin & sparse hair

• Personal history:– IUGR– 9mo: severe dehydration IV rehydration– 10mo: adenoidectomy, transmission deafness– Ophtalmologic abn., hyposalivation…

Case n° 1 (cont’d)

• Familial history– Familial atopy+++– Obesity tendancy – Mother: IUGR, abnormal dentition, hypotrichiosis

Diagnoses? Exams?

Case n° 1 (cont’d)

• GS disease: salivary glands biopsy: normal

• Auto-immune disease:– LE cells (-); Latex-WR (-); Anti-musle ab (-)– Prot. electrophoresis, Ig & Cp: Normal

• Hormonal deficiency– GH & T4-TSH: Normal

??

Patient had futures of Anhidrotic Ectodermal Dysplasia…

• Reduced sweating• Abnormal hair patterns: thin, sparse…• Conical or peg teeth

Clinical triad

• Genetic disorder • Defective development of teeth, hair, nails

& eccrine sweat glands:• Hypodontia/ Anodontia, Conical teeth• Hypotrichosis or alopecia• Hypohdrosis or anhidrosis

• Genetic background:– Inherited X linked form+++– Autosomal dominant (AD) & Autosomal recessive

(AR)

• Three interacting proteins– Ectodysplasin: Xq12-q13.1

– EDA-A1: essentiel for skin appendages– EDA-A2: development timing & completion

– EDAR: 2q11-q13– EDARADD: 1q42.2-q43

NEMO is critical for activation for a transcription factor, critical for immune responses

Help finding NEMO…

Hypothetic signalling of EDA1 & EDAR

Wisniewski et al. J Appl Genet 2002; 43(1)

Why are EDs so diverse?

• Same genes involved in devpt. of ectodermal structures

• Nature & location of mutation

• Syndromic forms (same genes involved in devpt. of other structures)

• EEC: Ectrodactyly, Ectodermal Dysplasia, Cleft/ lip palate

• SHFM: Split Hand/ Foot Malformations

• Hay-Wells syndrome• Rapp-Hodgkin syndrome…

Clinical diagnosis (1)

• Trichogram examination3 shaft abnormalities (Pili torti, Tricorrhexis nodosa, variable shaft thickness)

• Starch-iodide paper palm imprint

• Skin biopsy (horizontal section,palmar)

• Scalp biopsy

Rouse et al. Arch Dermatol 2004;140

6

3

0

7

N° s

ubje

cts

Affected subjects Unaffectedsubjects

Scalp Biopsy

Eccrine structures absentEccrine structures present

Rouse et al. Arch Dermatol 2004;140

Clinical diagnosis (2)

• Kabbaj et al. J Med Genet 1998; 35(12)• 14 family members, common ancestor• 6 deaths in early childhood/ dehydration• Hypotrichosis,Hypodontia, Anhidrosis

• Baala et al. Am J Hum Genet 1999; 64(2)• DNA collected in 32 members, 8 were affected• Linkage to chromosome 2q11-q13

Stéphane Anne Jérémy

Age at diagnosis

10 days 10 months 6 months

Presentation Severe obst. rhinitis

W & H: -3SD ENT sx

Other sx Hyperthermia, abn. swallowing

GERD+++, Oph. abn., Hyposalivation

Anorexia

DA + + +

Dentition Anodontia Hypodontia 2 conical incisors

Mother:Abn. dentitionAbn. hair

++

++

+0

Stéphane Anne Jérémy

SPT + + +

Total IgE 465 Normal 800-1300

Specific IgE - - ND

ND: not done

• Respiratory onset sx between 3-6 years• First repsiratory assessment at 2, 5 & 6 years

– IgA: -1,3 to -2SD except Anne; other normal.– Complement system normal

• Flexible endoscopy: Inflammatory pattern (I-II), Absence of mucosal secretions, Acquired ciliary abnormalities (viral)

11/1982 01/1990 04/1990 07/1991FVC - 2,01(81) 2,19(85) 2,47(89)RFC 0,605(106) 1,24(96) 1,24(93) -FEV1 - 1,38(66) 1,52(70) 1,77(76)MEF25-75 - 1,25(47) 1,44(54) 1,81(64)PEF - 2,81(67) 3,89(89) 4,61(99)MEF50 - 1,45(50) 1,69(56) 2,15(67)MEF25 - 0,61(41) 0,73(47) 0,89(54)Pulm. Res. 13,24(149) - - -DC 30(68) - - -ABG Hypoxia N N Hypoxia

() are % of theoric values

Severe Distal Obstruction, partially reversible

Conclusions

• Antenatal counselling+++• Fetoscopy: skin & palmar biopsy/ 20th gest.week

• cDNA probes gene mapping• Villous biopsy/10th gest.week

• But…sporadic cases have been described(de novo mutation)